Human cytomegalovirus (HCMV) is the leading cause of congenital viral infection in the U.S. affecting 1% of all live births. The most frequent sequela resulting from intrauterine HCMV infection is sensorineural hearing loss. It is estimated that of the 41,000 infants born each year with congenital HCMV infection in the U.S., approximately 5000 will develop hearing loss. In the majority of these children the hearing loss is progressive during the first three years of life. The broad objective of this project is to develop an understanding of the natural history and pathogenesis of hearing loss due to congenital HCMV infection. The specific aims are: 1) To further define the incidence and delineate the natural history of hearing loss including the type, severity, laterality, age of onset and progression in infants with congenital HCMV infection. This will be accomplished by following infants with congenital HCMV infection over time with serial audiologic assessments. 2) Investigation of maternal HCMV specific immunologic responses during pregnancy which are associated with hearing loss in the offspring. Qualitative differences were noted in pre- and postnatal HCMV specific antibody responses between women delivering infants with hearing loss as compared to mothers of infants with normal hearing. These observed differences along with previous studies suggested that involvement of the auditory system is associated with earlier acquisition of maternal and presumably fetal HCMV infection. Serial pre- and postnatal immune responses of mothers will be correlated with the hearing loss in the offspring with congenital HCMV infection to test this hypothesis 3) Examination of HCMV specific immunologic and virologic determinants which are associated with delayed onset and progressive hearing loss. Serial immunologic (cellular and antibody) and virologic studies (viremia and viruria) will be utilized to define the association between ongoing viral replication as a result of abnormal immune responses and the development of progressive hearing loss in children with congenital HCMV infection. These studies will clarify the role of congenital HCMV infection as a leading cause of congenital deafness. The definition of pre- and postnatal immunologic and virologic determinants of hearing loss will provide information that will serve as a foundation for efforts to prevent or reduce the incidence of this important public health problem.